BETA CATENIN SIGNALING DURING FEATHER TRACT DEVELOPMENT

羽管发育过程中的β连环蛋白信号传导

• 批准号: 6402701
• 负责人: BRUCE A MORGAN
• 金额: $ 26.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-10 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6402701
• 关键词: DNA binding protein; Vesiculovirus; avian leukosis virus; biological signal transduction; cadherins; chick embryo; developmental genetics; ectoderm; electroporation; gene expression; mitogens; molecular cloning; oncoproteins; polymerase chain reaction; protein tyrosine kinase; skin; transfection /expression vector; vertebrate embryology

A problem central to the generation of organs and organisms is the allocation of multipotent cells to different fates in appropriate positions and numbers. The interactions between intercellular signaling pathways which contribute to this process appear to be common to the generation of many embryonic structures. The feather field is well suited to study the early steps of pattern formation because the large and accessible fields of cells competent to participate in this process are amenable to manipulation both in vivo and in vitro. Feather buds are precisely patterned structures whose morphogenesis is mediated by co-ordinated activity of epithelial and mesenchymal signaling centers. Buds are positioned relative to each other in a precise array and any perturbation in the formation or activity of the signaling centers that organize the bud is readily detected as an interruption in the regularity of that array. The long term goal of this project is to employ the feather tract to dissect the interactions between signaling pathways that generate pattern in organs generated by epithelial mesenchymal interactions. The roles of several signaling molecules, including BMPs, FGFs and Notch and its ligands, have been partially elucidated. Recent work has demonstrated that activation of the beta-catenin signaling pathway is a crucial step in initiation of bud formation. This proposal focuses on the mechanisms by which activation of this pathway is localized during tract development. The effects of blocking this signaling pathway will be assessed to refine observations based on gain of function experiments. Members of the Wnt family can activate beta-catenin signaling, so their expression and activity during tract formation will be explored. The effects of retroviruses employed to alter the expression and activity of Wnts at different times and positions in the tract in ovo will be assessed at the morphological and molecular levels. The sequential roles of the beta-catenin pathway and the Wnts that activate it that are inferred from in vivo work will be tested in a series of in vitro experiments targeted to specific steps of tract development. Spatial or temporal differences in response to exogenous Wnts will be used to infer the interaction between this and other signaling pathways, and the roles of different TCFs and Grgs in modulating responsiveness to Wnts to pattern the tract will be investigated. This should enhance our understanding of the formation of many organs as well as suggest strategies to control the developmental defects and cancer that are caused by deregulated activity of the beta-catenin signaling pathway.

器官和生物产生的核心问题是将多能细胞分配给适当位置和数字的不同命运。 有助于此过程的细胞间信号通路之间的相互作用似乎是许多胚胎结构的产生。 羽毛场非常适合研究模式形成的早期步骤，因为有能力参与此过程的大型细胞领域可以在体内和体外操作。 羽毛芽是精确的图案结构，其形态发生是由上皮和间质信号传导中心协调活性介导的。 芽在精确的阵列中相对于彼此的位置，并且在信号传导中心的形成或活性中，组织芽的任何扰动很容易被视为该阵列规律性的中断。 该项目的长期目标是利用羽毛道来剖析上皮间质相互作用产生的器官中产生模式的信号通路之间的相互作用。 几种信号分子（包括BMP，FGFS和Notch及其配体）的作用已部分阐明。 最近的工作表明，β-catenin信号通路的激活是芽形成启动的关键步骤。 该提案重点介绍了该途径在道路发展过程中局部激活的机制。 阻止此信号通路的效果将根据功能实验的获取来评估以完善观察结果。 Wnt家族的成员可以激活β-catenin信号传导，因此将探索其在形成过程中的表达和活性。 将在形态和分子水平上评估使用逆转录病毒来改变OVO中不同时间和位置的WNT的表达和活性的影响。 β-catenin途径的顺序作用以及从体内工作推断出的WNT的依次作用将在针对特定特定步骤开发的特定步骤的一系列体外实验中进行测试。 对外源WNT响应的空间或时间差异将用于推断该信号通路和其他信号通路之间的相互作用，并且将研究不同TCF和GRG在调节对Wnts对wnts进行模式的响应性中的作用。 这将增强我们对许多器官形成的理解，并提出控制由β-catenin信号通路失调活性引起的发育缺陷和癌症的策略。